Identification of the global miR-130a targetome reveals a role for TBL1XR1 in hematopoietic stem cell self-renewal and t(8;21) AML.

Autor:	Krivdova G; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A5, Canada., Voisin V; The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada., Schoof EM; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Marhon SA; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Murison A; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., McLeod JL; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Gabra MM; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada., Zeng AGX; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A5, Canada., Aigner S; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA., Yee BA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA., Shishkin AA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA., Van Nostrand EL; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA., Hermans KG; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Program of Developmental & Stem Cell Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G0A4, Canada., Trotman-Grant AC; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Mbong N; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Kennedy JA; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Division of Medical Oncology and Hematology, Sunnybrook Health Sciences Centre, Toronto, ON M4N3M5, Canada., Gan OI; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Wagenblast E; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., De Carvalho DD; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A8, Canada., Salmena L; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada., Minden MD; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Bader GD; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A5, Canada; The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5T 3A1, Canada., Yeo GW; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA., Dick JE; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A5, Canada. Electronic address: john.dick@uhnresearch.ca., Lechman ER; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada. Electronic address: eric.lechman@uhnresearch.ca.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2022 Mar 08; Vol. 38 (10), pp. 110481.
DOI:	10.1016/j.celrep.2022.110481
Abstrakt:	Gene expression profiling and proteome analysis of normal and malignant hematopoietic stem cells (HSCs) point to shared core stemness properties. However, discordance between mRNA and protein signatures highlights an important role for post-transcriptional regulation by microRNAs (miRNAs) in governing this critical nexus. Here, we identify miR-130a as a regulator of HSC self-renewal and differentiation. Enforced expression of miR-130a impairs B lymphoid differentiation and expands long-term HSCs. Integration of protein mass spectrometry and chimeric AGO2 crosslinking and immunoprecipitation (CLIP) identifies TBL1XR1 as a primary miR-130a target, whose loss of function phenocopies miR-130a overexpression. Moreover, we report that miR-130a is highly expressed in t(8;21) acute myeloid leukemia (AML), where it is critical for maintaining the oncogenic molecular program mediated by the AML1-ETO complex. Our study establishes that identification of the comprehensive miRNA targetome within primary cells enables discovery of genes and molecular networks underpinning stemness properties of normal and leukemic cells. Competing Interests: Declaration of interests G.W.Y. is a cofounder, a member of the board of directors, on the scientific advisory board, an equity holder, and a paid consultant for Locanabio and Eclipse Bioinnovations. G.W.Y. is a visiting professor at the National University of Singapore. G.W.Y.’s interests have been reviewed and approved by the University of California, San Diego, in accordance with its conflict-of-interest policies. E.L.V.N. is a co-founder, a member of the board of directors, on the SAB, an equity holder, and a paid consultant for Eclipse Bioinnovations. E.L.V.N.’s interests have been reviewed and approved by the University of California, San Diego, in accordance with its conflict of interest policies. (Copyright © 2022. Published by Elsevier Inc.)
Databáze:	MEDLINE
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